ABSTRACT
BackgroundOrgan transplant recipients are at high risk of viral infections but show lower humoral vaccine responsiveness than immunocompetent individuals. HLA evolutionary divergence (HED) quantifies the sequence differences between homologous HLA alleles and reflects the breadth of the immunopeptidome presented to T lymphocytes. MethodsWe retrospectively investigated the impact of HED on humoral response to SARS-CoV-2 mRNA vaccine in 310 liver transplant recipients (undetectable anti-spike IgG titers considered as no response, [≤]250 BAU/mL as moderate response, >250 BAU/mL as strong response) and to Hepatitis B virus (HBV) vaccine in 424 liver transplant candidates (anti-HBs IgG <10 mIU/mL considered as no response, 10-100 mIU/mL as moderate reponse, [≥]100 mIU/mL as strong response). HED between aligned allele pairs at HLA-A, -B, -DRB1 and- DQB1 loci were measured as a continuous metric using the Grantham distance. The impact of HED on vaccine responses was analyzed through ordinal logistic regression and inverse probability weighting approach based on generalised propensity scores. FindingsFor both vaccines, HED at the DQB1 locus, but not at other loci, was significantly higher in responders than in others, independent of covariates associated to the response (age, time since transplant, hemoglobin levels, combined graft, immunosuppression with steroids or mycophenolate for SARS-CoV-2 vaccine; age, gender, and liver disease for HBV vaccine). InterpretationDQB1 HED is a critical determinant of humoral response to vaccines in liver transplant recipients. This metric could guide the design of future vaccines as it predicts the magnitude of the repertoire of vaccine-derived peptides presented to CD4 helper T cells. FundingInstitut National de la Sante et de la Recherche Medicale (INSERM)
ABSTRACT
Optimal vaccination and immunotherapy against coronavirus disease COVID-19 relies on the in-depth comprehension of immune responses determining the individual susceptibility to be infected by SARS-CoV-2 and to develop severe disease. We characterized the polarity and specificity of circulating SARS-CoV-2-specific T cell responses against whole virus lysates or 186 unique peptides derived from the SARS-CoV-2 or SARS-CoV-1 ORFeome on 296 cancer-bearing and 86 cancer-free individuals who were either from the pre-COVID-19 era (67 individuals) or contemporary COVID-19-free (237 individuals) or who developed COVID-19 (78 individuals) in 2020/21. The ratio between the prototypic T helper 1 (TH1) cytokine, interleukin-2, and the prototypic T helper 2 (TH2) cytokine, interleukin-5 (IL-5), released from SARS-CoV-2-specific memory T cells measured in early 2020, among SARS-CoV-2-negative persons, was associated with the susceptibility of these individuals to develop PCR-detectable SARS-CoV-2 infection in late 2020 or 2021. Of note, T cells from individuals who recovered after SARS-CoV-2 re-infection spontaneously produced elevated levels of IL-5 and secreted the immunosuppressive TH2 cytokine interleukin-10 in response to SARS-CoV-2 lysate, suggesting that TH2 responses to SARS-CoV-2 are inadequate. Moreover, individuals susceptible to SARS-CoV-2 infection exhibited a deficit in the TH1 peptide repertoire affecting the highly mutated receptor binding domain (RBD) amino acids (331-525) of the spike protein. Finally, current vaccines successfully triggered anti-RBD specific TH1 responses in 88% healthy subjects that were negative prior to immunization. These findings indicate that COVID-19 protection relies on TH1 cell immunity against SARS-CoV-2 S1-RBD which in turn likely drives the phylogenetic escape of the virus. The next generation of COVID-19 vaccines should elicit high-avidity TH1 (rather than TH2)-like T cell responses against the RBD domain of current and emerging viral variants.
